The wendigo resembles a gaunt, emaciated humanoid with ashy gray skin, long bony arms, a pot belly and a skull-like face topped with scant strands of long, stringy hair, with mouth filled with long, jagged teeth. They have large claws on the tips of each finger.

They exhibit similar characteristics to ghouls, such as radiation resistance. They do not engage in combat with ghouls when they're near.

Wendigos are fast and can deal a large amount of damage in a very short amount of time. They get close and can be hard to hit without V.A.T.S. if using a firearm. Wendigos will not run away if the player character climbs onto objects or furniture, but will continue to screech. During combat, wendigos may let loose a piercing shriek that doesn't damage the player but will possibly attract a horde of feral ghouls to their location.

There is a large possibility for a ravenous/scorched wendigo to spawn at Hawke's Refuge. It is one of three creatures that can spawn in a small cavern off of the main cave. The other creatures that may be found there are a withered feral ghoul or a putrid glowing one. It will always be one of these three.

A wendigo is created through radiation according to "The Curse Of The Wendigo" holotape radio play accompanying issue #1 of Tales from the West Virginia Hills, also called "Curse of the Wendigo."

Wendigos have an acidic bite. When the player character scraps a wendigo's teeth, they gain acid from them.

Edie's note, found on a woman's corpse on Wendigo Cave, tells of her and her partner, Morris Stevens, committing cannibalism. After being exiled from the Gourmands for eating fellow gang members, a short amount of time later he became greedy (in folklore, a sign of becoming a wendigo), and began to watch her. She is discovered dead and Morris is not found.

In Algonquin folklore, a wendigo is a malevolent spirit that is frequently associated with winter, coldness, famine, and starvation. It possesses and transforms human beings who have committed sins such as selfishness, greed, gluttony, murder, and especially cannibalism. The spirit then forces them to consume human flesh, turning them into a monster with an insatiable hunger for it. The wendigo are also part of the traditional belief system of many Algonquin-speaking cultures, such as the Ojibwe, Eastern Cree, Saulteaux, Westmain Swampy Cree, Naskapi, and Innu peoples. Though the folklore among cultures varies somewhat, the wendigo is commonly seen as an evil, cannibalistic, supernatural entity.